When there is a damage in a tissue or a cell or an infection by a foreign substance in a human body (e.g., bacteria, molds, virus, various allergy-inducing materials), it usually entails an inflammatory response expressed as a series of complex physiological responses such as activation of enzyme, secretion of inflammation-mediating materials, infiltration of body fluid, cell movement, and damage of tissues that are related to all sorts of inflammation-mediating factors and immunocytes in local blood vessels, body fluid, and as external symptoms such as erythema, edema, and pyrexia. Normally, inflammatory responses remove external sources of infection, reproduce damaged tissues, and recover the function of life, but when an antigen is not removed or inflammatory responses occur excessively or continuously due to intrinsic substances, inflammatory responses become the main pathological symptoms of diseases (hypersensitive disease, chronic inflammation) and the main obstacles in the processes of treatment such as blood transfusion, drug administration and organ transplantation, and the like.
The effects of factors involved in inflammatory responses relating to the present invention are described as follows.
Complement system is a major factor of body fluid, which activates and amplifies inflammation at the early stage of an immune response. Active proteins (anaphylatoxins; C3a, C4a, C5a) and conjugated proteins (membrane attack complex (MAC)) produced in the activation process of complement system are related to various inflammatory diseases (rheumatic arthritis, lupus erythematosus, adult respiratory distress syndrome, Alzheimer's disease) and often become the direct causes of superacute rejections in organ transplantation.
ICAM-1 is a typical protein of cell adhesion molecule group expressed on the surface of endothelial cells. Normally, it is expressed in a very low level, however, when it is stimulated by inflammation-mediating molecules of cytokines such as TNF-α, interferon-γ, and interleukin-1β, the level of expression is accelerated rapidly to play a role in adhering inflammatory cells such as mononcytes or lymphocytes that move in blood and in moving the inflammatory cells to the inflammatory tissues. Therefore, the expression of ICAM-1. plays an important rote in the amplification of inflammation when inflammatory cells move and gather on the inflammatory tissues at its early stage.
VCAM-1 is one of cell adhesion molecule groups expressed on the surface of endothelial cells. The expression increases rapidly in the endothelial cells of blood vessels when atherosclerotic lesions are produced in the animal model (apolipoprotein-E-deficient mice, ApoE−/−) analogous with the progress of human atherosclerosis. And the increase of VCAM-1 expression is directly correlated with the concentration of cholesterol—low density lipoprotein (cholesterol-LDL) in the plasma. Therefore, when atherosclerotic lesions are induced, VCAM-1 expressed in the endothelial cells of blood vessels adheres monocytes/and lymphocytes in the blood and those inflammatory cells gather under endothelial cells of blood vessels, thus playing an important role in development of atherosclerotic lesions.
NO is produced together with L-citrulline after L-arginine is oxidized by nitric oxide synthase (NOS). NO is a mediating-molecule concerned with vasodepression, adhesion and coagulation of blood platelets, neurotransmission, movement of digestive organism, and erection of penis by affecting the blood vessel system. And NO protects against a microbial infection by being produced not only in inflammatory cells but also in nonimmune cells. Meanwhile, the inducible-NOS (iNOS), one of NOS participating in producing NO is independent of calcium or calmodulin and expressed by stimulation of lipopolysaccharide (LPS) and cytokines (IFN-γ, TNF and the like). Because cyclooxygenase-2 (COX-2) is also activated by this stimulation thereby producing inflammation-mediating molecules, prostaglandins, there is close correlation between the expression of iNOS and COX-2, and thus produced NO also affects the expression of COX-2. Production of NO in macrophages is selectively induced by the expression of iNOS, and thus induces activation of other inflammatory responses. Therefore, NO is an important factor of inflammatory diseases.
Atherosclerosis is a disease with arteries becoming hardened caused by genetic conditions related to lipid metabolism and environmental conditions such as eating habits, smoking and lack of exercise, and it can result in diseases of circulatory system such as a heart disease and a vascular disease of brain. A hypothesis about early outbreak of atherosclerosis is “response-to-injury” hypothesis and this means that the endothelial cells of blood vessels become dysfunctioned by being unable to maintain normal homeostasis as the result of genetic changes, peroxides, hypertension, glycosuria, increase in plasma homocysteine concentration and microbial infection, and the like. When the endothelial cells of blood vessels become dysfunctioned, the expression of cell adhesion molecules becomes high, cell transmission increases, and then adhesion of immunocytes, platelets and fat, and transmission to the tissue begin to increase. Inflammatory responses such as secretion of an inflammation-mediating factor and a growth factor of the immunocyte result in generation of atherosclerotic lesions. Wherein, as a result of oxidation, saccharide bonding, accumulation and glycoprotein bonding, low-density lipoprotein (LDL) in blood becomes modified-LDL (MLDL), which induces stimuli and damage of the endothelial cells of blood vessels and smooth muscles. On this account, when the expression of VCAM-1 on the endothelial cells and release of inflammation-mediating factor of inflammatory cells are promoted, LDL is flowed and accumulated under the endothelial cells, and accumulated LDL and oxidized MLDL repeat the process of inducing inflow and activation of immunocytes such as macrophages, T-lymphocyte and the like, and consequently inflammation of lesion is promoted. Thereafter, the speck is necrotized by macrophage inflowed to the lesion, and hydrolase released from lymphocyte, inflammation-mediating factor and growth factor. Through the repeating processes of inflow of monocytes to the region of the necrotized focus, movement and differentiation of smooth muscle, as well as formation of fibrous tissues, lesion tissue grows into a complex structure of fibrous tissues covered with fibroid materials in necrotic tissue having MLDL as a core part. Thrombus is produced from the grown lesion tissue, arteries become hardened and diseases of circulatory system such as hindrance of blood flow occur. Therefore, atherosclerosis occurs when the amount of fat such as cholesterol and LDL in the blood is high, but it does not occur simply by accumulation of fat. Rather, atherosclerosis is a typical inflammatory response that endothelial cells, macrophages and lymphocytes correlate with a series of process of inflow and accumulation of fat under the endothelial cells of arteries, progress of lesion thereafter and finally cell necrosis.
Agastache rucosa is a perennial plant, which belongs to Labiatae family and is distributed in Northeast Asia that includes Korea, Japan, China, and etc. In Korea, it mostly grows wild in southern area or cultivated in some areas. In Chinese medicine, the aerial part of this plant is called Patcholi (other name of Agastache rugosa) and a Chinese book, “Myoneubyolok”, says “it removes bad energy from our body and toxin by configuration of the ground, and cures cholera morbus, that is, cures one's sickness inside and intestinal convulsion”. Among the ordinary people, the leaf is used as a savor material in various soups such as loach soup and the flower is used as a honey source.
The study on components of Agastache rugosa reports that there are kinds of essential oil, sesquiterpene, diterpene, triterpene, flavonoid, phenylpropanoid and carotenoid. The study on physiological activity of Agastache rugosa reports antibacterial activity of the extract [Phytother. Res. 14(3), 210-212, 2000; J. Food Sci. Nutr. 4(2), 97-102, 1999], antiviral activity [Arch. Pharm. Res. 22(5), 520-523, 1999; U.S. Pat. No. 5,776,462], and inhibitory activity against monoamine oxydase [The Pharmaceutical Society of Korea 42(6), 634-638, 1998]. And also, antibacterial [Zhongguo Yaozue Zazhi 35(1), 9-11, 2000; Weishengwuxue Zazhi 18(4), 1-4, 16, 1998] and mosquito avoidance activity of essential oil [Chinese Pat. No. 1044205], anticancer activity of carotenoid [The Korean Society of Pharmacognosy 30(4), 404-408, 1999], anticancer [J. Nat. Prod. 58(11) 1718-1821, 1995] and antiviral activity of diterpene [Arch. Pharm. Res. 22(1), 75-77, 1999], and antiviral activity of phenylpropanoid [Arch. Pharm. Res. 22(5), 520-523, 1999], anti-oxidation [The Korean Society of Agricultural Chemistry and Biotechnology 42(3), 262-266, 1999] and anti-complement activity [The Korean Society of Pharmacognosy 27(1), 20-25, 1996; The Korean Society of Agricultural Chemistry and Biotechnology 39(2), 147-152, 1996] have been reported. However, there is no report of study yet on anti-inflammatory and anti-atherosclerotic activity of extract of Agastach rugosa neither at home nor abroad.
Tilianin, on the other hand, has been reported to be present in various plants as glucose-glycoside compound of acacetin, one of flavonoids.

The study on physiological activity of tilianin reports anti-oxidation activity [J. Food Sci. Nutr. 4(1999), 221-225; Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem 36B(1997), 1201-1203] and no inhibitory activity of xanthine oxidase [J. Nat. Prod. 51(1988), 345-348]. But, there is no report of the study yet on anti-inflammatory and anti-atherosclerotic activity of tilianin neither at home nor abroad.